Hematopoietic Progenitor Cell Mobilization for Autologous Stem Cell Transplantation in Multiple Myeloma in Contemporary Era

Accepted Manuscript “Hematopoietic Progenitor Cell Mobilization for Autologous Stem Cell Transplantation in Multiple Myeloma in Contemporary era” Satyam Arora, MD, Navneet S. Majhail, MD, MS, Hien Liu, MD PII:

S2152-2650(18)31458-7

DOI:

https://doi.org/10.1016/j.clml.2018.12.010

Reference:

CLML 1249

To appear in:

Clinical Lymphoma, Myeloma and Leukemia

Received Date: 10 October 2018 Revised Date:

10 December 2018

Accepted Date: 12 December 2018

Please cite this article as: Arora S, Majhail NS, Liu H, “Hematopoietic Progenitor Cell Mobilization for Autologous Stem Cell Transplantation in Multiple Myeloma in Contemporary era”, Clinical Lymphoma, Myeloma and Leukemia (2019), doi: https://doi.org/10.1016/j.clml.2018.12.010. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Title Page Title: “Hematopoietic Progenitor Cell Mobilization for Autologous Stem Cell Transplantation in Multiple Myeloma in Contemporary era”

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Authors: Satyam Arora, MD1; Navneet S Majhail, MD, MS2; Hien Liu, MD3 Affiliations: 1Department of Transfusion Medicine, Super Specality Paediatric Hospital and Post Graduate Teaching Institute, Noida, Uttar Pradesh, India; 2Blood and Marrow Transplant Program, Cleveland Clinic, Cleveland, USA: 3 Blood and Marrow Transplant and Cellular

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Therapy, Moffitt Cancer Center, Tampa, Florida, USA

cell dose

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Key Words: HPC mobilization, chemo-mobilization, G-CSF, GM-CSF, Plerixafor, CD34+

Conflict of Interest: The authors have no relevant financial conflicts of interest to report

Word Count:

Text: 2212 words; Tables: 4; Figures: nil

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References: 74

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Abstract: 117 words;

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Corresponding Author:

Satyam Arora, MD

Department of Transfusion Medicine, Super Specality Paediatric Hospital and

Post Graduate Teaching Institute, Noida, Uttar Pradesh, India +919971107774

[email protected]

ACCEPTED MANUSCRIPT Abstract Successful stem cell mobilization and adequate harvesting of hematopoietic progenitor cells (HPC) is necessary for patients with multiple myeloma undergoing high dose chemotherapy and autologous stem cell transplantation (ASCT). Several advances have increased the efficiency and yield of HPC collection methods, and sufficient CD34+ cell collection can be

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expected for most myeloma patients who are considered to be ASCT candidates. However, some patients fail to mobilize and collect adequate number of CD34+ cells. Our review aims to discuss various mobilization strategies available for mobilizing HPCs in multiple myeloma patients and the evolution of these strategies over time. We also discuss the concept of

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mobilization failure, factors predictive of poor mobilization, and potential mobilization

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regimens for such patients.

Key Words: Multiple Myeloma, Hematopoietc Stem Cell Transplant, Engraftment,

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Mobilization, Autologous Transplant, GCSF, Plerixafor

ACCEPTED MANUSCRIPT Introduction Autologous stem cell transplantation (ASCT) is part of standard frontline therapy for most patients with multiple myeloma.1,2 Adequate hematopoietic progenitor cell (HPC) collection is necessary for proceeding to transplantation. The target for CD34+ cell collection

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for a single ASCT is generally accepted to be 3-6×106 CD34+ cells/kg and a dose below 2×106 CD34+ cells/kg can have a deleterious effect on engraftment.3–5 Approximately 5-40% of patients fail to collect this minimum threshold dose.6 Our review discusses the available

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protocols for HPC mobilization, special scenarios encountered in myeloma patients, and

HPC Mobilization in Myeloma

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potential strategies for managing initial mobilization failures.

Mobilization can be clinically defined as the release of hematopoietic stem and progenitor cells into peripheral blood following treatment with cytokines and/or

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chemotherapy. The circulating HPCs are then collected via apheresis, and can be used for marrow reconstitution following high-dose chemotherapy administered as part of ASCT. The goal of mobilization is to cost-effectively collect sufficient HPCs using the least number of

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apheresis procedures and with minimal mobilization related complications.

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The collection target for CD34+ cells and the method of mobilization utilized for a given patient depends on several factors such as the number of transplants planned (single or tandem ASCT), plan to store cells for a possible subsequent transplant, and presence of risk factors that may predict poor mobilization (see below). While a minimum cell dose of 2×106 CD34+ cells/kg is recommended for single ASCT, the optimal dose is not yet defined (Table 1). In patients with lymphoma, higher cell doses have been associated with improved survival after ASCT;7 however, does not show benefits in terms of survival with faster hematologic recovery, fewer incidence of infectious and bleeding complications after a single transplant.8

ACCEPTED MANUSCRIPT The International Myeloma Working Group (IMWG) suggests a minimum target of 4×106 CD34+ cells/kg and, if feasible, an average of 8–10×106 CD34+ cells/kg should be collected, allowing most myeloma patients to undergo two ASCTs during the course of their disease, in case, the first transplant is unsuccessful.3 The American Society for Blood and Marrow

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Transplantation (ASBMT) recommends a minimum cell dose of 2×106 CD34+ cells/kg for a single ASCT, and collection of >5×106 CD34+ cells/kg if feasible.4

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There are various approaches to mobilization, and the method that is ultimately used for a patient depends on patient/disease factors including CD34+ collection target, potential

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for adequate mobilization, ability to receive further chemotherapy and disease status as well as institutional considerations (familiarity with mobilization regimens, historical practices & available resources in institution). Mobilization strategies presently used routinely in clinical practice include steady state mobilization using cytokines, chemo-mobilization or use of

Steady-State Mobilization

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CXCR4 inhibitor plerixafor.

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Granulocyte-colony stimulating factor (G-CSF) and granulocyte macrophage-colony

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stimulating factor (GM-CSF) have been used alone and in combination for mobilization at doses ranging from 3-24 µg/kg/day as subcutaneous injections. When compared with GMCSF alone; G-CSF alone has shown higher yield with fewer toxicities, earlier neutrophil and platelet recovery and less transfusion requirements.9–12 The recommended and most commonly used dose of G-CSF in practice is 10 µg/kg/day. Once daily dosing schedule of GCSF has similar mobilization outcomes compared to twice daily dosing. given for four consecutive days with apheresis beginning on the fifth day.

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It is typically

ACCEPTED MANUSCRIPT Pegfilgrastim is a pegylated form of G-CSF used as fixed single dose (12 mg subcutaneous injection) for mobilization. It is less commonly used than non-pegylated GCSF, but in early clinical experience has been shown to lead to predictable mobilization with similar yields and on apheresis days.14–17 However, its cost-effectiveness in comparison to

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non-pegylated G-CSF needs to be determined. Other growth factors and cytokines that have been investigated for steady-state mobilization include biosimilar filgrastim (manufactured by recombinant DNA technology from E. coli, Tbo-filgrastim),18 glycosylated recombinant

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G-CSF filgrastim (lenograstim),19–22 recombinant GM-CSF (molgramostim),22 glycosylated GM-CSF (sargramostim),23 and recombinant human stem cell factor (ancestim).24–26

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Biosimilar G-CSF formulations have been introduced and tested for HPC mobilization. Biosimilar G-CSF has bioequivalent pharmacokinetic properties and comparable quality, safety and efficacy to the originator formulation.27–29 Given their lower cost, many transplant centers have switched to using bio-similar G-CSF formulations for

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HPC mobilization.

In the United States, cytokines approved by the Food and Drug Administration (FDA) for mobilizing HPCs for collection by leukapheresis include Neupogen® (filgrastim [G-

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CSF], Amgen) and Zarxio® (biosimilar, filgrastim-sndz [G-CSF], Sandoz). The FDA label

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for Granix (Tbo-filgrastim, Sicor Biotech) does not include HPC mobilization as an indication and the FDA label for Neulasta® (pegfilgrastim [G-CSF], Amgen) specifically states that it is not indicated for HPC mobilization for hematopoietic cell transplantation.

Chemo-Mobilization Chemotherapy based mobilization is another option, especially in patients with active disease, as it can achieve both anti-tumor and mobilizing effects. Chemotherapy and subsequent myelosuppression stimulates HPC proliferation resulting in a larger pool of

ACCEPTED MANUSCRIPT progenitor cells in peripheral blood compared to baseline state. Chemotherapy that is used for this purpose may be incorporated into the initial disease-specific induction or salvage therapy regimen, or may be administered separately from standard therapy. Several studies illustrate

and hematopoietic growth factors (Table 2).

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that there is improved efficiency of mobilizing regimens when containing both chemotherapy

At the same time, the increase in peripheral blood HPC yields and are often accompanied by greater toxicity as a result of the concurrent administration of

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chemotherapy.30 There is the possibility that chemotherapy given as part of mobilization may reduce graft contamination by malignant cells, but studies have demonstrated no impact on

survival, or overall survival.31

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transplantation outcomes, such as complete response rate, time to progression, event-free

The choice of chemotherapy is based on patient disease characteristics and on institutional practices. High-dose cyclophosphamide and etoposide are commonly used drugs

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for mobilization in myeloma patients where these agents are administered after completion of induction therapy and specifically for the purpose of HPC mobilization.32,33 Myelomaspecific chemotherapy regimens that have been used for mobilization include CAD

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(cyclophosphamide, doxorubicin, dexamethasone) and PACE (platinum, doxorubicin,

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cyclophosphamide, etoposide). G-CSF is started after chemotherapy completion and patients undergo apheresis as they recover from their nadir.

Plerixafor

Plerixafor (AMD3100; Mozobil®) is a selective and reversible CXCR4 inhibitor. The interaction between CXCR4 and its ligand SDF-1 results in chemotaxis, an increase in the number of HPCs and their migration into the bone marrow microenvironment.34 The impairment of this interaction by plerixafor directs HPCs into the circulation.

ACCEPTED MANUSCRIPT In a pivotal phase III trial, patients with multiple myeloma received G-CSF (10 µg/kg) subcutaneously daily and were randomized to additional plerixafor (240 µg/kg) or placebo subcutaneously (upfront mobilization).35 A total of 71.6% (106/148) patients in the plerixafor group and 34.4% (53/154) patients in the placebo group met the primary endpoint of

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collection of ≥6×106 CD34+ cells/kg in ≤2 apheresis. Fifty-four percent of plerixafor-treated patients reached target after one apheresis compared to GCSF-placebo-treated patients where 56% required 4 aphereses to reach target. Other studies have also shown better achievement

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of collection targets, lower mobilization failure rates, and fewer apheresis sessions compared with G-CSF alone (Table 3). Plerixafor is approved by the FDA for HPC mobilization in

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myeloma patients in combination with G-CSF. Costs associated with the upfront use of both plerixafor and G-CSF has been a concern, and some studies show comparable or lower costs with the use of both agents upfront in comparison to chemotherapy mobilization and G-CSF alone, while others report mobilization without plerixafor as being more cost-effective36–39.

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In order to improve cost-effectiveness, several studies have evaluated the pre-emptive addition of plerixafor to steady-state G-CSF in patients with risk factors for poor mobilization, known to mobilize poorly based on pre-apheresis peripheral blood CD34+ cell

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counts or who collect poorly based on early daily apheresis yields (pre-emptive mobilization).

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Costa et al. have reported pre-established peripheral blood CD34+ thresholds at which plerixafor could be added to improve collection efficiency and reduce the cost of mobilization attempts.40,41 This resulted in significantly lower mobilization failure rates of 2% to 3% compared with the 22% observed with chemotherapy mobilization. Based on present evidence, it is reasonable to consider upfront use of plerixafor in addition to G-CSF for HPC mobilization in patients at high risk for mobilization failure (see below) and where real time CD34+ cell count assessment is not available. Plerixafor can be

ACCEPTED MANUSCRIPT reserved for pre-emptive mobilization or for salvage after mobilization failure in all other scenarios. Mobilization Failures Poor mobilizers are often defined as patients with a CD34+ stem cell count

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<20×106/L in peripheral blood at maximum stimulation or a collection yield of <2×106 CD34+ cells/kg with a maximum of four apheresis procedures.42 Approximately 15% of patients undergoing HPC mobilization meet the criteria for poor mobilizers.43 Of note, it may

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be difficult to collect sufficient HPCs for a second ASCT in some patients with peripheral blood CD34+ levels of >20×106/L. These patients are often referred to as inadequate

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mobilizers.

The risk factors for mobilization failure are listed in Table 4, and can be treatmentrelated, patient-related or related to the mobilization regimen itself. Clinical variables generally are poor predictors of mobilization efficiency. Peripheral blood CD34+/µl count

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significantly correlates with the collected CD34+ cell count in the final apheresis product and is a better predictor of mobilization.44 Although thresholds vary, the widely accepted level to start apheresis is when peripheral blood CD34+ count of ≥20/µl is achieved. Generally

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CD34+ cell count of <5/µl is associated with poor yield. CD34+ cell count between 10/µl and 20/µl, may be an indication for the pre-emptive use of plerixafor. Larger processing volumes

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can also be considered in such patients and have shown encouraging results.44. Strategies to manage patients who are mobilization failures or inadequate mobilizers

include dose escalation of cytokines, and remobilization with a more intensive or novel regimen, or bone marrow harvesting.5 Cytokines should not be used alone,;combining cytokines with plerixafor and/or chemotherapy have shown promising results.5 In patients who have received G-CSF alone as their first mobilization regimen, a rest period of 2-4

ACCEPTED MANUSCRIPT weeks followed by a repeat attempt at mobilization using upfront plerixafor and G-CSF or chemotherapy is usually successful.5 Failure to collect sufficient number of HPCs for ASCT in the first attempt is associated with delay in treatment, patient inconvenience and risk of toxicity and additional

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costs. With the presently available options for mobilization, it is imperative that collection centres establish protocols to identify patients who are at risk for mobilization failure and manage them appropriately. At the Cleveland Clinic, we use plerixafor and G-CSF upfront in

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patients who are at high risk for inadequate mobilization (age >60 years, prior therapy with alkylators or prolonged lenalidomide exposure, extensive bone marrow disease, radiation to

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the pelvis, hypocellular marrow or profound thrombocytopenia). For myeloma patients who are ‘standard risk’ for mobilization, we use G-CSF only and plerixafor is added preemptively in case of low day 1 peripheral blood CD34+ count (<20/µL) or inadequate yield by day 2 of apheresis.

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Factors affecting the efficiency of mobilization in myeloma Induction therapy for myeloma

Lenalidomide is an effective and commonly used agent for induction in patients with

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myeloma. It has been reported to have a negative impact on HPC collection.45 Both chemotherapy and plerixafor-containing mobilization strategies have been shown to

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overcome this negative effect and result in successful collections46. Bortezomib containing regimens do not show significant impact on stem cell yields and failure rate although some trials have indicated otherwise.47,48 Irrespective, early mobilization and stem cell collection (after 4-6 cycles of initial therapy) is recommended in myeloma patients who are considered to be candidates for ASCT.3,4

ACCEPTED MANUSCRIPT Age and comorbidities Low bone marrow reserve of progenitor cells in bone marrow with advancing age is considered as one of the main reasons for poor mobilization in elderly. On the other hand, protocols also exclude patients over the age of 70 for transplant due to the potentially greater

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risk of regimen-related toxicities. A limited marrow reserve can be indicated by a low platelet count prior to mobilization, low bone marrow cellularity, and baseline low peripheral blood CD34+ numbers.49–53 Diabetes mellitus and impaired glucose tolerance have also been

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identified as independent risk factors for poor mobilization. The mechanisms underlying these findings are thought to be due to a low peripheral CD34+cell count in these patients and

associated with diabetes mellitus.54,55

Bone marrow and disease status

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alteration of the hematopoietic niche probably via a sympathetic denervation syndrome

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Induction therapy can induce hematologic toxicity to the marrow, resulting in varying degrees of cytopenia at the time of mobilization. Hence a compromised marrow is less likely to mobilize the HPCs adequately and could result in mobilization failure. GCSF mobilization

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of such marrow would induce release of mature mononuclear cells.56

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Baseline and treatment related conditions have also been known to influence the harvest efficiencies. Osteolytic lesions at the time of diagnosis have been reported to be associated with collection failure.57 Appropriate response of osteoclasts to G-CSF is important for mobilizing stem cells; with advanced osteolytic lesions there is a preexisting increase in activity of osteoclasts which is marginally influenced by G-CSF.

ACCEPTED MANUSCRIPT Conclusion Mobilization strategies have evolved with understanding of the myeloma biology as well as the interaction of stem cell niche with the mobilizing agents. Many newly diagnosed myeloma patients do not mobilize adequately and fail to collect the stem cells. The successful

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collection of adequate number of CD34+ cells depends on many factors apart from the mobilization strategy adopted alone. Hence these mobilizing strategies should be

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individualized before initiating the treatment plan for an ASCT.

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analysis. Bone Marrow Transplant. 2015;50(6):813–7.

ACCEPTED MANUSCRIPT Table 1: Dose of CD34+ cells for autologous progenitor cell transplantation for a single transplant in myeloma patient with possible clinical outcomes5 Possible clinical outcome

>3-5 x 106/Kg

Optimal dose for a single transplant

≥2 x 106/Kg

Minimum dose, though higher dose is better for patients with lymphoma

1.5-2 x 106/Kg

Associated with delayed engraftment

≤1 x 106/Kg

More chances of erythrocyte transfusion and graft failure

M AN U

SC

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CD34+ Cell Dose

Table 2: Mobilization efficiencies with failure rates (FR) while applying various chemotherapy regimens and G-CSF for patients with Myeloma

CD 34+

Study

Regimen

TE D

Author

Yield

FR

NE

PE

(%)

(days)

(days)

12

11

11

13

FD

(x 106/kg)

Studies showing GCSF induced mobilization post induction chemotherapy

MJ Bargetzi et al59

I Gojo et al60

Annunziata M et al62

M

N=22; GCSF

4.85

N=74; CY7+GCSF/GMCSF

8.6

NA 32.4

14

7.8

10

M

N=42; CY4+GCSF/GMCSF

13.4

N=19; VNB+GCSF

11.1

Prospective

M N=12; CY+GCSF

20.5

N=28; CY+GCSF

21.8

Prospective

NA 11

12

NA

NA

14

12

0

19

14

14

NA

NA

3

12

13

3

12

13

NA

M N=49; CY+Eto+GCSF

A Corso et al61

6.8

Retrospective

AC C

O Filtroussi et al58

N=18; HD-CY +GCSF

Prospective

EP

A Alegre et al10

N=106; 2xDCEP(iv)+GCSF

22.39 5.2

Prospective

10 M

N=46; 2xDCEP(sh)+GCSF

6.98

N=37; CY+VNB+GCSF

9.2

Prospective

11 M

N=41; CY+GCSF

8.7

ACCEPTED MANUSCRIPT

Lin et al64

N=55; LD-CY+GCSF

0

10

17

N=78; LD-CY

6.93

19.2

11

14

N=5; CY/DOX

7.4

20

11

14.5

N=10; GCSF

3.61

50

12

12

13

19

O4

N=519; GCSF Retrospective

NA

N=35; CY4+GCSF (250µg/kg)

Prospective

NA

NA

13

16.4

12

13

14.7

16

N=37; CY4+GMCSF (250µg/kg)

12.8

4.17

M AN U

N=351; GCSF (10 µg/kg)

SC

M

RCT

N=200; GCSF (16-24 µg/kg)

Prospective

N=206; CY(1.5)+GCSF(5 µg/kg) S Fruehauf et al68

18

24.9

Studies showing GCSF and chemotherapy induced mobilization

J de la Rubia et al67

14

N=68; ID-CY+GCSF

N=449; CY/Eto +GCSF

Arora M et al66

6 M

Prospective

Uy GL et al65

7.8

Prospective

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Hamadani et al63

4.38

M

4.98

N=26: CAD+ Pegfilgrastim Prospective

NA

3.1

Prospective

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C Hart et al69

Prospective

N=140; DT-PACE+ Pegfilgrastim

NA

N=12; IEV+ GCSF

12.6

Prospective

AC C

M Martino et

70

EP

N=14; IEV+ GCSF+EPO

N=40; CY2+Biosimillar GCSF N=37; CY2+Orignator GCSF

11

12

(over all)

11

12

NA

NA

12

14

13

21

14

13

17*

17^

13*

16^

17

10.9*

3.6

0

10.7*

2.7

2.5

11

13

2.7

11

13

N=97; DT-PACE+Filgrastim Tricot G et al

NA

M

N=52; CAD+ Filgrastim

17

18

M

NA

O6 15.4 11.5 M 12.3

FD-Failure Definition; FR-Failure Rate; NE- Neutrophil Engraftment (>500x106/L); PE-Platelet Engraftment (> 20,000x106/L); NA- Data Not Available; M- Minimal Number of > 2x106 CD34+ cells collected; O4- Optimal dose of >4x106/kg; O6- Optimal dose of >6x106/kg; HD-CY- High dose cyclophosphamide (4gm/m2 iv); GCSF- Granulocyte Colony Stimulating Factor; CYcyclophosphamide; CY7- cyclophosphamide (7gm/m2); CY4- cyclophosphamide (4gm/m2); GMCSF- Granulocyte Macrophage Colony Stimulating Factor; VNB- Vinorelbine; Eto-Etoposide; DCEP(iv)- Dexamethasone, Cyclophosphamide-400mg/m2, Etoposide 40mg/m2,Cisplatin 10mg/m2; DCEP(sr)- Dexamethasone, cyclophosphamide 700mg/m2, Etoposide 100mg/m2,Cisplatin25mg/m2; LD-CY- Cyclophophamide 1-2g/m2; ID-CY- Cyclophophamide 7g/m2; CY/DOXCY+Doxorubicin, Dexamethasone, GCSF. CAD- Cy, Adriamycin, Dexamethasone; DT-PACE-Dexamethasone, Thaladomide,

Cispplatin, Adriamycin, CY, Etoposide; IEV- Ifosfamide, Etoposide, Epirubicin; CY2- cyclophosphamide (2gm/m2).* Neutrophil Engraftment (>1000x106/L); ^ Platelet Engraftment (> 50,000x106/L).

ACCEPTED MANUSCRIPT

Table 3: Mobilization regimens and failure rates (FR) addition of plerixafor with various GCSF regimens with chemotherapy for ASCT in myeloma patients CD 34+ Study

Regimen

Yield (x 106/kg)

N Flomenberg et al71 Kumar et al46

RCT; DB

N=148; P+GCSF

12.97

N=154; Placebo+GCSF

7.31

Prospective

N=9; P

2.27

Prospective

N= 39; L+P+GCSF

Phase 3

N=10; VNB+P+GCSF

A Antar et al73 G Tricot et al72

Prospective

N=10; VNB+P

Phase 2

N=10; P+GCSF

Retrospective

3.55

9.5 9.4

N=10; VBN+GCSF

8.9

N=56; CY+GCSF

15.5

N=27; P+GCSF

7.5

Prospective

Poor Mobil; N=10; P+GCSF

5.8

Phase 2

Sec Mobil; N=10; P+GCSF

7

NE

PE

(%)

(days)

(days)

11

18

11

18

NA

M

0

10.5

21

3

14

15.5

0

11

14

20

11

14

0

11

15

20

11

12

4

11

12

11.2

12

12

30

10-19

16

20

11-23

19

M

10.6

M AN U

A Schmid et al72

FR

M

SC

JF DiPersio et al35

FD

RI PT

Author

M

M

M

FD-Failure Definition; FR-Failure Rate; NE- Neutrophil Engraftment (>500x10 /L); PE-Platelet Engraftment (> 20,000x106/L);

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NA- Data Not Available; M- Minimal Number of > 2x106 CD34+ cells collected; O6- Optimal dose of >6x106/kg; GCSFGranulocyte Colony Stimulating Factor, P-Plerixafor; CY- cyclophosphamide; L-Linolidamide; VNB- Vinorelbine. RCT-

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Randomized Controlled Trial; DB- Double Blind.

ACCEPTED MANUSCRIPT Table 4: Factors related to risk of mobilization failure •

AC C

EP

TE D

M AN U

SC

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Treatment related o High numbers of prior chemotherapy (≥ 2 lines of chemotherapy) o Exposure to alkylating agents, purine analogs or lenalidomide, Figure 1: o Mobilizing for Autologous Extended strategies field radiotherapy to marrowHematopoietic containing sites,Cell Transplant for myeloma • Patient Related patients o Older age (> 65yrs) o Female sex o Diagnosis of Non Hodgkin lymphoma (NHL) o Presence of osteolytic lesion o Diabetes and smoking • At the time of Mobilization o Low Hemoglobin and low baseline platelet number (< 1,00,000/mL) o Longer time from last chemotherapy to mobilization initiation o Bone marrow infiltration with the primary disease (cellularity < 30%) at the time of mobilization o Pre-apheresis PB CD34 cell numbers (< 20x106 /µl) o Low day 1 Apheresis yield o Collection procedure
Timing of apheresis,
Type of cell separator used,
The rate and the volume of whole blood processed